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Evans Syndrome

Bisitopenia dan pansitopenia yang disebabkan oleh berbagai kondisi, yang paling sering yaitu anemia aplastik, kekurangan vitamin B12, kekurangan asam folat, penyakit lupus (SLE), paroxysmal nocturnal hemoglobinuria, kanker darah (leukemia, multiple myeloma), dan limfoma.

Untuk usia, yaitu 17 tahun, kondisi yang paling mendekati yaitu anemia aplastik. 

Kondisi ini dapat dialami oleh orang dari berbagai usia. 

Anemia aplastik merupakan kondisi di mana tubuh berhenti memproduksi sel-sel darah baru.

Akibatnya tubuh merasa lelah, dan rentan mengalami infeksi dan perdarahan.

Perdarahan yang paling umum ditemukan berupa memar tanpa sebab dan jelas atau perdarahan gusi pada saat menyikat gigi.

Bisitopenia: Tidak Semua Jumlah Sel Darah Turun Pada Evans Syndrome

Bisitopenia adalah penurunan dua dari tiga komponen sel darah (angka eritrosit, angka leukosit dan trombosit). 

Dua dari tiga komponen tersebut dapat mengalami penurunan jumlah jika terjadi suatu kelainan hematologi maupun kelainan organ yang berhubungan dengan sel darah. 

Penurunan dapat terjadi pada jumlah eritrosit dan jumlah trombosit dengan jumlah leukosit yang normal atau meningkat, penurunan jumlah eritrosit dan leukosit dengan angka trombosit normal. 

Bisitopenia dapat menggambarkan suatu proses yang dilalui sebelum terjadinya pansitopenia.

Pansitopenia, yaitu penurunan jumlah ketiga komponen sel darah. 

Jadi, bisitopenia dapat berkembang menjadi pansitopenia.

Salah satu penyakit yang murni terdapat bisitopenia adalah Evans Syndrome.

Evans Syndrome merupakan penyakit autoimun di mana tubuhnya menbentuk antibodi yang menyerang sel darah merah dan trombosit. 

Secara genetik penyakit ini masih belum bisa di identifikasi keterkaitannya.

Pada penelitian sindrom ini didapatkan angka harapan hidup 3 tahun pada 42 pasien, dan 3 pasien meninggal, 20 pasien menjadi penyakit aktif dan sedang menjalani pengobatan, dan 5 pasien memiliki penyakit tetap selama 1,5 bulan sampai 5 tahun.

Pada pasien ini terjadi AIHA (Autoimun Hemolytic Anemia) dan trombositopenia dengan penyebab yang tidak diketahui. 

Auto antibodi secara langsung melawan antigen spesifik dari sel darah merah, trombosit atau neutrofil. 

Gejala yang didapatkan tergantung dari jenis sel darah yang mengalami penurunan. 

Misalnya purpura, ptekie, perdarahan sebagai tanda trombositopenia dan sebagai tanda anemia penderita mengeluhkan lemas dan mudah lelah.

Wang et al mengatakan bahwa pada penderita evan syndrome terjadi penurunan kadar serum IgG, IgM, IgA. 

Keadaan penurunan jumlah sel darah pada EvansSyndrome dikaitkan dengan kelainan pada sel T karena didapatkan penurunan sel Thelper dan peningkatan sel T supresor.

Penatalaksanaan penderita penyakit ini masih sangat minimal. 

Pemberian steroid mampu menekan sistem imun karena memang penyakit ini didasari oleh autoimun.

Sehingga dengan pemberian steroid yang bekerja sebagai imuno supresan diharapkan terjadi penekanan pada pembentukan auto antibodi.
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Practice Essentials
Evans syndrome is the presence of simultaneous or sequential direct Coombs-positive autoimmune hemolytic anemia (AIHA) in conjunction with immune-mediated thrombocytopenia, with no known underlying etiology.

Signs And Symtoms
Manifestations of Evans syndrome may include the following, in descending order of frequency:
  1. Thrombocytopenia
  2. Anemia
  3. Neutropenia
  4. Pancytopenia
Signs of thrombocytopenia include purpura, petechiae, and ecchymoses. Signs of anemia include pallor, fatigue, and light-headedness. Jaundice may indicate hemolysis.

Potential complications of Evans syndrome include the following:
  1. Hemorrhage with severe thrombocytopenia
  2. Serious infection in patients with neutropenia
See Presentation for more detail.

Diagnosis
Laboratory studies that may be considered include the following:
  1. Complete blood count (CBC)
  2. Reticulocyte count
  3. Coombs test (direct antiglobulin test)
  4. Tests for antineutrophil, and antiplatelet antibodies
  5. Lupus antibody (lupuslike inhibitor) and antinuclear antibody (ANA) tests
  6. Measurement of serum immunoglobulins
  7. Flow cytometry of blood samplesGene mutation studies
Bone marrow aspiration helps reveal aplastic anemia or an infiltrative disorder. It is usually indicated for excluding infiltrative processes in patients who present with pancytopenia.

See Workup for more detail.

Management
Medical therapy is the mainstay of management. In patients admitted for severe anemia or thrombocytopenia, the following are indicated:
  1. Stabilization of respiratory and cardiovascular functions
  2. Transfusion of blood products, if needed
  3. Pharmacologic therapy
Commonly used agents are as follows:
  1. Prednisone (most commonly used first-line agent)
  2. Intravenous immune globulin (IVIg; for those with persistent immune cytopenia and those who require prolonged or high doses of steroids)
Other pharmacologic therapies that have been tried include the following:
  1. Danazol
  2. Cyclosporine
  3. Azathioprine
  4. Cyclophosphamide
  5. Vincristine
  6. Rituximab
  7. Alemtuzumab
Additional therapies have included the following:
  1. Splenectomy (has no clearly established role in treatment but may be considered in refractory cases)
  2. Autologous and allogeneic stem cell transplantation
See Treatment and Medication for more detail.

Background
Evans syndrome is the coexistence of simultaneous or sequential direct Coombs-positive autoimmune hemolytic anemia (AIHA) with immune-mediated thrombocytopenia. In the initial description by Evans et al in 1951, the anemia and thrombocytopenia varied with respect to time of onset, course, and duration. Spontaneous remission and exacerbation were common, and a few patients had neutropenia.

Although Evans syndrome seems to be a disorder of immune regulation, the exact pathophysiology is unknown, and the underlying etiology is unclear. Autoantibodies targeting different antigenic determinants on red blood cells (RBCs) and platelets are assumed to cause isolated episodes of hemolytic anemia and thrombocytopenia, respectively. The typical clinical course is chronic and relapsing, and therapy is generally progressive and of poor outcome.

Pathophysiology
The exact pathophysiology of Evans syndrome is unknown. Non-cross-reacting autoantibodies are directed against antigens specific to RBCs, platelets, or neutrophils. Wang et al demonstrated decreased serum levels of immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) in these patients. The cytopenias that occur with Evans syndrome may be related to T-cell abnormalities; decreases in helper T cells and increases in suppressor T cells were noted in these patients.

Savasan et al observed that more than half of the patients with Evans syndrome had evidence of lymphoid hyperactivity. Teachey et al demonstrated that more than half (58%) of the patients with Evans syndrome might have autoimmune lymphoproliferative syndrome (ALPS), a novel finding with potentially important therapeutic implications.

Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked overaccumulation of mature lymphocytes and autoimmune disease in mice. Some study results suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in severe ALPS in humans.

Teachey et al screened 12 children by using flow cytometry for CD4/ CD8 (double-negative) T cells and using the definitive test for ALPS (ie, defective in vitro Fas-mediated apoptosis). Six patients had elevated numbers of double-negative T cells and defective Fas-mediated apoptosis, and 1 had a borderline elevation; thus, 7 patients with Evans syndrome had evidence suggestive of ALPS, which, in turn, suggests that there may be some overlap between Evans syndrome and ALPS. This may explain the severe clinical course in some patients with Evans syndrome.

Etiology
The etiology of Evans syndrome remains unknown. Autoantibodies are directed against antigens specific to RBCs, platelets, or neutrophils, but these autoantibodies do not cross-react.

Many patients have associated disorders (eg, systemic lupus erythematosus [SLE] and other autoimmune diseases, chronic lymphadenopathy, or hypogammaglobulinemia). Acquired cytopenias occur in association with-linked agammaglobulinemia, common variable immunodeficiency, and IgA deficiency.

Evans syndrome has been diagnosed in 1 child with insulin-dependent diabetes mellitus, in another after an autologous bone marrow transplant for recurrent Hodgkin disease, and in 1 child with celiac disease.

Most patients with Evans syndrome have decreased levels of serum IgG, IgM, and IgA and decreased in vitro synthesis of IgG, IgM, or both.

Decreased helper T cell populations and increased suppressor T cell populations that are similar to levels found in congenital hypoplastic anemia and amegakaryocytic thrombocytopenia have been observed. This finding has led to speculation that the cytopenias in Evans syndrome may relate to T-cell abnormalities.

As noted (see Pathophysiology), numerous patients with Evans syndrome may have ALPS.

The role of childhood immunizations in the development of Evans syndrome has been investigated, but no specific associations have been reported. However, case reports suggest that immunizations may trigger the development of this disease in susceptible individuals.

Epidemiology
United States Statistics
In the United States, Evans syndrome is uncommon but not rare; its exact frequency is unknown. Familial occurrence is rare.

Pirofsky estimated the minimal annual incidence of immune hemolytic anemia to be 1 case per 80,000 US residents (mostly adults). In a combined series of 1064 patients with childhood immune thrombocytopenia, only 9 had autoimmune hemolytic anemia associated with immune thrombocytopenia; however, thrombocytopenia occurs relatively often in patients with autoimmune hemolytic anemia. Frequencies of 1.6-59.4% have been reported in adults.

Pui et al first described 7 children with Evans syndrome out of 164 cases of immune thrombocytopenia and 15 cases of AIHA. Habibi et al observed that 10 of 46 children with prolonged chronic AIHA had thrombocytopenia.

International Statistic
In a report from Malaysia by Ng, Evans syndrome was diagnosed in 12 of 220 adult patients with immune thrombocytopenia and 102 with AIHA.

Age-related demographics
Evans syndrome occurs in individuals of all ages. In a 1997 survey of North American pediatric hematologists, the median reported age at diagnosis was 7.7 years (range, 0.2-26.6 years).  This late presentation age may indicate that the disease was undiagnosed until the second presentation of cytopenia, which usually occurred months to years after the first presentation. Evans syndrome in adults has been anecdotally reported.

Sesual differences in incidence
No sesual predilection is known in Evans syndrome. AIHA affects boys more frequently than girls, in a ratio of 1.4:1. Among adults, however, AIHA affects women more often than men. In a study by Genty et al, 67% of cases occurred in women.

Racial differences in incidence
Of 42 patients reported in a national survey, 29 were white, 7 were black, and 6 had other racial backgrounds. This distribution could suggest either a preponderance among whites or a reporting bias. As individual conditions, AIHA and immune thrombocytopenia have no racial predilection.

Prognosis
The characteristic clinical course of Evans syndrome includes periods of remission and exacerbation. Patients rarely do well without treatment, and responses to therapy are variable and often disappointing. On occasion, Evans syndrome can be fatal.

Recurrences of thrombocytopenia and anemia are common, as are episodes of hemorrhage and serious infections. In a national survey by Mathew et al, recurrences of thrombocytopenia were documented in 60% of Evans syndrome patients; the number of reported recurrent episodes was 1-20. AIHA recurred in 31% of patients; the number of episodes ranged from 1 to 8. Neutropenia recurred in 15% of patients.

Treatment occasionally provides complete resolution. In a median follow-up study of 42 patients (age, 4 months to 18.9 years) that spanned 3 years, 3 patients (7%) had died, 20 (48%) had active disease and remained on some treatment, and 5 (12%) had persistent disease but were not receiving any treatment. The remaining 14 (33%) had no evidence of disease for 1.5 months to 5 years (median, 1 year).

In the national survey, each patient received a median of 5 (range, 1-12) treatment modalities, either in combination or sequentially. Only 1 patient received no treatment; this patient’s hemoglobin levels were 9-13.2 g/dL and platelet counts were 9-208,000/µL during follow-up examinations over 11 years.

Long-term survival data are limited. In patients followed for a median range of 3-8 years, mortality ranged from 7-36%. The main causes of death were hemorrhage and sepsis. None of these patients developed any malignancy.

Patient Education
Patients and their families must be educated about the chronic nature of Evans syndrome, which can include periods of remission and exacerbation. It is important that the clinician explain potential adverse effects of medications, especially long-term steroids, whenever a steroid is administered to treat an exacerbation.
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Evans Syndrome Market Research Report - Global Forecast till 2023
Evans syndrome Market Information: by diagnosis (blood test, bone marrow biopsy, antibody assays, computed tomography (CT) scan, flow cytometry), treatment (Splenectomy, Pharmacologic, Biologic therapy, Stem Cell), end user – Global forecast till 2023.
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Market Scenario
Evans syndrome (ES), is an autoimmune disorder characterized by the subsequent or simultaneous development of autoimmune hemolytic anemia, and immune thrombocytopenia. It is classified as primary or secondary based on its association with others diseases, such as primary antiphospholipid syndrome, systemic lupus erythematous (SLE), Sjögren syndrome, Hodgkin lymphoma, IgA deficiency, and chronic lymphocytic leukemia.

According to the Centers for Disease Control & Prevention, autoimmune disorder is the third most common category of disease in the United States after heart disease and cancer. It is reported that it affects approximately 5%–8% of the population i.e. 14–22 million persons.

The severity and symptoms of Evans syndrome vary greatly from one person to another. Some patients with Evans syndrome may first show the high destruction of red blood cells (RBCs), known as anemia, and others may first show low levels of platelets, known as thrombocytopenia. Low levels of white blood cells (WBSs), known as neutropenia, is less common in individuals with Evans syndrome than thrombocytopenia or anemia.

Notably, growing public awareness is the key factor driving the Evans syndrome market. Nowadays, people are becoming more aware of the different types of autoimmune disorders. Government and other different organizations have started educating people about hygiene and diseases through seminars, and conferences. People are becoming more aware and conscious of the diseases. Thus, increasing awareness has provided a push to the growth of the market.

Various other factors such as increasing incidents of autoimmune disorders, increasing government assistance, improving regulatory framework, increasing automation of laboratories and rising funding and reimbursement are continuously contributing to the growth of the global Evans syndrome market.

Despite these drivers, there are some issues associated with Evans syndrome market. Some of the challenges in research and development, side-effects of treatment, the presence of misbranded and spurious drugs, and poor healthcare system in low and middle-income countries, may hinder the growth of the market to an extent.

It is estimated that the Evans syndrome market is expected to grow at a CAGR 10.2% during the forecast period of 2017-2023.
Intended Audience
  1. Pharmaceutical Companies
  2. Research and Development (R&D) Companies
  3. Diagnostic Laboratories
  4. Government Research Institute
  5. Academic Institutes and Universities
Segmentation
The global Evans syndrome market is segmented on the basis of diagnosis, treatment, and distribution channels.

On the basis of the diagnosis, the market is classified as blood test, bone marrow biopsy, antibody assays, computed tomography (CT) scan, flow cytometry of double-negative T cells, and others. The blood test is further segmented into complete blood count (CBC), and direct antiglobulin test.

On the basis of the treatment, the market is classified as pharmacologic therapy, splenectomy,
Biologic therapy, stem cell transplantation, and others. The pharmacologic therapy is further segmented into Prednisone and intravenous immunoglobulin (IVIg) therapy. The biologic therapy is segmented into Rituximab and others.

On the basis of the distribution channel, the market is segmented into hospitals, clinics, diagnostic centers, drug stores, pharmacies, and others.

Regionla Analysis
The Americas dominate the Evans syndrome market owing to the rising awareness among people, and high healthcare expenditure. According to the Centers for Disease Control and Prevention in 2015, the total health expenditure in the United States was reported to be USD 3.2 trillion and hospital care accounted for a share of 32.3%.

Europe holds the second position in the Evans syndrome market. It is expected that the support provided by the government bodies for research & development and improvement in reimbursement policies in the healthcare is likely to drive the market of Europe region.

Asia Pacific is the fastest growing Evans syndrome market owing to a huge patient pool and developing healthcare technology. Healthcare expenditure is also improving in various Asia Pacific countries. According to the Australian Institute of Health and Welfare in the years 2015-2016, the total health expenditure was USD 170.4 billion, which is 3.6% higher than the expenditure of 2014-2015.

The Middle East & Africa holds the lowest market due to lack of technical knowledge and poor medical facilities.

Key Players
Some of key the players in the global Evans syndrome market are Pfizer, Merck & Co., Sanofi, Astellas Pharma, Inc., GlaxoSmithKline plc, Novartis AG, Enzon Pharmaceuticals, Inc., Bayer AG, Sigma-Aldrich, Abbott Laboratories, Eli Lily and Company, BD, ChemoMetec A/S, and Others.

Research Methodology:
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